Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies
Amy Easton, Marianne L. Jensen, Congwei Wang, Peter Hagedorn, Yu-Wen Li, Michael R. Weed, Jere E. Meredith, Valerie Guss, Kelli Jones, Martin B. Gill, Carol Krause, Jeffrey M. Brown, Lisa Hunihan, JoAnne E. Natale, Alda Fernandes, Yifeng Lu, Joe Polino, Mark Bookbinder, Greg Cadelina, Yulia Benitex, Ramola Sane, J. S. Morrison, Dieter M. Drexler, Stephen E. Mercer, Charlotte Bon, Nikhil J. Pandya, Ravi Jagasia, Tai-Hsien Ou Yang, Tania Distler, Fiona Grüninger, Michael Meldgaard, Marco Terrigno, John E. Macor, Charles F. Albright, James Loy, Anja M. Hoeg, Richard E. Olson, Angela Cacace
Abstract
locus resulted in the identification of hot spots for activity in the 3' UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well tolerated and produced a robust, long-lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post injection and corresponded with tau protein reduction in the cerebrospinal fluid (CSF). Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.